A molecule that cells normally use to fight viruses is also involved in keeping cancer cells alive, researchers at UT Southwestern Medical Center have discovered.

The anti-viral molecule, called TBK-1, was found to be essential for cancer cells to live, so blocking it might point to a treatment for fighting cancer, the researchers report in today's issue of Cell.

"We got the surprise that this mechanism is involved in cancer cell survival, even though it's normally involved in immune response," said Dr. Michael White, associate professor of cell biology. "We found something a little bit different — an Achilles' heel of cancer cells that's apparently broadly conserved among many types of solid tumors."

Using cultured human cells, the researchers set out to study enzymes known to be involved in keeping cancer cells alive and proliferating. They soon narrowed the focus to one called RalB. This molecule is part of the Ras family of enzymes, which are mutated in 30 percent of all cancers and in 90 percent of pancreatic cancers.

The UT Southwestern scientists knew that RalB interacts with a protein complex called the exocyst, which helps small secretory packets in cells fuse to the cell membrane. The team isolated this complex, then chemically analyzed the proteins attached to it.

One protein they found on the exocyst, TBK-1, is known to be involved in cells' anti-viral response.

"There was nothing known about that mechanism to suggest how TBK-1 could drive cancer cell survival," Dr. White said.

The researchers found that TBK-1 is turned off in healthy cells unless the immune response is stimulated but was always active in the cancerous cells they studied. When they blocked the function of TBK-1 in both the cancerous and healthy cells, cancer cells died while healthy cells survived.

A German research team has studied clinical samples of tumors and found elevated levels of TBK-1, Dr. White said.

The TBK-1 action is part of an immune reaction called the "host defense response," which is distinct from the "adaptive" immune process, in which the body creates new antibodies against invading pathogens. A great deal is currently understood about how the adaptive immune system fights cancer and also helps create tissue environments permissive to cancer, Dr. White said, but a cancer-promoting role for the host defense response has not been previously seen.

It's a straightforward matter to block the action of TBK-1, so this might be a promising avenue for new cancer treatments, Dr. White said. Because that would also interfere with the body's immune function, however, a balance would have to be found between killing cancer cells and compromising a patient's ability to fight disease.

UT Southwestern researchers are now looking for chemicals that block TBK-1. They are also screening cancer cells for similar biochemical pathways essential to their survival but not essential in normal cells.

"This is making us think that there are many other surprises awaiting discovery regarding biological systems that are inappropriately subverted during development of cancer," Dr. White said.

Other UT Southwestern researchers involved in the study were Dr. Yu-chen Chien, postdoctoral researcher in cell biology; Dr. Sungchan Kim, senior research associate in biochemistry; Ron Bumeister, research scientist in physiology; Dr. Yueh-Ming Loo, postdoctoral researcher in microbiology; Dr. Sung Won Kwon, a former postdoctoral researcher in biochemistry now at Seoul National University; Cynthia Johnson, a microbiology student in the Medical Scientist Training Program; Dr. Michael Gale, associate professor of microbiology; and Dr. Yingming Zhao, associate professor of biochemistry. Researchers from the Institut Curie in France and the University of Iowa also participated.

The work was supported by the National Institutes of Health, the Robert E. Welch Foundation, the Susan G. Komen Breast Cancer Foundation and the Department of Defense Breast Cancer Research Program.

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